5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structural modifications at the tryptophan domain
Jm. Bartolome-nebreda et al., 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structural modifications at the tryptophan domain, J MED CHEM, 42(22), 1999, pp. 4659-4668
Analogues of the previously reported potent and highly selective CCK1 recep
tor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhyro
pyrido-[1,2-c]pyrimidine (2a) were prepared to explore the structural requi
rements at the Boc-tryptophan domain for CCK1 receptor affinity. Structural
modifications of 2a involved the Trp side chain, its conformational freedo
m, the Boc group, and the carboxamide bond. Results of the CCK binding and
in vitro functional activity evaluation showed three highly strict structur
al requirements: the type and orientation of the Trp side chain, the H-bond
ing acceptor carbonyl group of the carboxamide bond, and the presence of th
e Trp amino protection Boc. Replacement of this acid-labile group with 3,3-
dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to anal
ogues 14a and 15a, which retained a high potency and selectivity in binding
to CCK1 receptors, as well as an in vivo antagonist activity against the a
cute pancreatitis induced by caerulein in rats. Oral administration of comp
ounds 14a and 15a also produced a lasting antagonism to the hypomotility in
duced by CCK-8 in mice, suggesting a good bioavailability and metabolic sta
bility.